ES2803248T3 - 2-perfluorohexyl octane for ophthalmic administration - Google Patents

Abstract

An ophthalmic composition comprising the compound characterized by the general formula CF3 (CF2) 5 (CH2) 7CH3 and CF3 (CF2) 5-CH (CH3) - (CH2) 5-CH3 in which n is 5 and m is 5.

Description

DESCRIPTION

2-perfluorohexyl octane for ophthalmic administration

Field

The present invention belongs to the field of semi-fluorinated compounds, their compositions and their use as a particular medicine for ophthalmic administration.

Background

Semi-fluorinated alkanes are compounds made up of at least one non-fluorinated hydrocarbon segment and at least one perfluorinated hydrocarbon segment. The linear unbranched semi-fluorinated alkanes of the general formula CF ³ (CF ² ) ⁿ (CH ² ) ^m CH ³ , where n and m are integers indicating the number of carbon atoms of the respective segment are described for various applications, for example commercially for retinal fold removal and re-applications, for long-term tamponade as a substitute for vitreous humor (H. Meinert et al, European Journal of Ophthalmology, Vol. 10 (3), pp. 189-197, 2000) and as solutions wash for residual silicon oil after vitreo-retinal surgery.

Semi-fluorinated alkanes of formula CF ³ (CF ² ) ⁿ (CH ² ) ^m CH ³ are described in other applications.

Document WO 2011/073134 discloses solutions of cyclosporine in semi-fluorinated alkanes of formula CF ³ (CF ² ) ⁿ (CH ² ) ^m CH ³ , optionally in the presence of a co-solvent such as ethanol, where the semi-fluorinated alkane functions as a vehicle of liquid drug administration for cyclosporine for the topical treatment of keratoconjunctivitis sicca.

WO 2014/041055 describes mixtures of semi-fluorinated alkanes of formula CF ³ (CF ² ) ⁿ (CH ² ) ^m CH ³ (which can alternatively be expressed as F (CF ² ) ⁿ (CH ² ) ^m H). These mixtures are described as ophthalmically applicable as tear film substitutes or for the treatment of patients with dry eye syndrome and / or meibomian gland dysfunction.

A frequently used nomenclature for semi-fluorinated compounds having linear and branched segments is FnHm, where F means a perfluorinated hydrocarbon segment, H means a non-fluorinated segment, and n and m define the number of carbon atoms in the respective segment. For example, F3H3 is used for perfluoropropylpropane, CF ³ (CF ² ) ² (CH ² ) ² CH ³ , that is, 1-perfluoropropylpropane.

Semi-fluorinated alkanes of the general formula CF ³ - (CF ² ) ⁿ -CH (CH ³ ) - (CH ² ) ^m -CH ³ have not been described, in particular for ophthalmic applications. Therefore, it is an object of the invention to provide such compounds, in particular with regard to their use in compositions, especially with utility in the field of ophthalmic applications.

Summary of the invention

In a first aspect, the invention relates to compositions comprising a semi-fluorinated compound characterized by the general formula CF ³ - (CF ² ) ⁿ -CH (CH ³ ) - (CH ² ) ^m -CH ³ in which n is 5 and m is 5. Preferably, these compositions are in the form of a liquid, wherein the compositions comprise at least 1% by weight, in particular from 1% by weight to 5% by weight, of a compound characterized by CF ³ - ( CF ² ) ⁿ -CH (CH ³ ) - (CH ² ) ^m -CH ³ where n is 5 and m is 5.

In another aspect, the present invention relates to compositions comprising said compound in the form of transparent liquid solutions, and also compositions consisting essentially of said compound and optionally one or more lipophilic liquid constituents.

In yet another aspect, the invention provides compositions comprising said compound for use in the treatment of dry eye disease and / or Meibomian Gland Dysfunction and any symptoms and conditions associated therewith, comprising administering said composition by Topically to the lacrimal sac, interior of the eyelid, ocular surface or ophthalmic tissue.

In yet another aspect, the present invention provides a kit comprising compositions of the present invention held in a container comprising a dispersion medium adapted for topical administration of the composition to the eye or ophthalmic tissue.

Brief description of the drawings

Figure 1 is a graph showing the relative evaporation time of compositions consisting of CF ³ (CF ² ) ⁵ (CH ² ) ^z CH ³ and CF ³ - (CF ² ) ⁵ -CH (CH ³ ) compounds. - (CH ² ) ⁵ -CH ³ as a function of the percentage of the last compound in the composition (indicated by the solid circle and dotted line in the graph), and for comparison of the relative evaporation time of compositions consisting of the CF compounds ³ (CF ² ) ³ (CH ² ) ⁴ CH ³ and CF ³ - (CF ² ) ³ -CH (CH ³ ) - (CH ² ) ² -CH ³ as a function of the percentage of the last compound in the composition (indicated by the transparent circle and the dashed line in the graph).

Figure 2 is a graph showing the refractive index determined for compositions consisting of the compounds CF ³ (CF ² ) ⁵ (CH ² ) ⁷ CH ³ and CF ³ - (CF ² ) ⁵ -CH (CH ³ ) - (CH ² ) ⁵ -CH ³ as a function of the percentage of the last compound in the composition.

Figure 3 is a graph showing the refractive index determined by compositions consisting of the compounds CF ³ (CF ² ) ³ (CH ² ) ⁴ CH ³ and CF ³ - (CF ² ) ³ -CH (CH ³ ) - (CH ² ) ² -CH ³ as a function of the percentage of the last compound in the composition.

Figure 4 is a graph depicting measurements of corneal erosion size (mm ² ) during the three-day course of an Ex Vivo Eye Irritation Test (EVEIT) compared to compositions CF ³ (CF ² ) ⁵ (CH ² ) ⁷ CH ³ and CF ³ - (CF ² ) ⁵ -CH (CH ³ ) - (CH ² ) ⁵ -CH ³ , a standard hyaluronic reference and a positive control of 0.01% BAC.

Detailed description of the invention

In a first aspect, the invention refers to a semi-fluorinated compound characterized by the general formula CF ³ - (CF ² ) ⁿ -CH (CH ³ ) - (CH ² ) ^m -CH ³ in which n is 5 and m is 5 .

Alternatively, the compound of the invention may also generally be referred to as 2-perfluorohexyloctane, based on the hydrocarbon alkane as the root.

The present compound is characterized by a stereocenter at the 2-alkyl position. As understood herein, the general formula encompasses both enantiomers, enriched mixtures of the two enantiomers, as well as the racemic mixture. Compounds as defined above have been found to provide a number of unexpected benefits, as described below. They are particularly useful when provided as compositions such as for medical applications, in particular for topical administration, such as topical ophthalmic administration.

The present invention relates to compositions comprising these semi-fluorinated compounds characterized by the general formula CF ³ - (CF2) ⁿ -CH (CH ³ ) -CH ² ) ^m -CH ³ as defined above, preferably in liquid form, for example formulated to be administered as a liquid solution. In optional embodiments, the compositions can be formulated to be administered as a gel, suspension, microemulsion, or an aerosol. Preferably the compositions are provided in sterile form.

In a particularly preferred embodiment, the compositions comprise a semi-fluorinated compound characterized by the general formula CF3- (CF2) n-CH (CH3) - (CH2) m-CH3 where n is 5 and m is 5 is in liquid form and comprises at least 1% by weight of the compound, in particular 1% by weight to 5% by weight, based on the total weight of the composition. In another embodiment, the composition may comprise between about 3% by weight to 5% by weight, or about 5% by weight to 10% by weight, or up to 25% by weight of the compound based on the total weight of the composition. In one of the preferred embodiments, the composition as defined above is formulated as a clear, liquid solution. In this context, transparency means the absence of dispersed solid or liquid particles that cause turbidity. In other words, such a clear solution is a pure single-phase liquid system, except that minor and technically irrelevant amounts of particulate impurities may be present. Furthermore, the composition is preferably formulated as a liquid solution exhibiting a refractive index that is close to that of water which is 1.333 at room temperature (RT). In a particularly preferred embodiment, the refractive index of the liquid solution is within the range of about 1.30 to about 1.35 at 20 ° C, as determined by means of a refractometer.

The compositions that have been defined above also comprise additional excipients as required or as useful such as one or more acids, bases, electrolytes, buffers, solutes, antioxidants, stabilizers, and if required, preservatives. In a preferred embodiment, the compositions defined above are substantially free of water and / or substantially free of a preservative, such as benzalkonium chloride.

In another preferred embodiment, the composition of the invention is formulated as a clear liquid solution that is substantially free of the following: (a) a polymer, (b) a perfluorinated compound and / or (c) a dissolved pharmacologically active ingredient that is not a semi-fluorinated alkane. In another embodiment, the composition as described herein may be substantially free of a pharmacologically active ingredient, in any form, and other than a semi-fluorinated alkane.

As understood herein, the term "substantially free" in reference to a constituent of the composition refers to the presence of said constituent in no more than trace amounts and that if present in trace amounts the constituent provides no technical contribution. to composition.

Examples of polymers that are preferably absent in the compositions of the invention include silicone polymers (polymerized siloxanes), polyether polymers, and fluorinated and perfluorinated derivatives thereof.

Examples of perfluorinated compounds, ie compounds in which all hydrogen atoms are substituted by fluorine, and which are preferably absent in the compositions of the invention include perfluoroalkanes such as perfluorodecalin, as well as halogenated perfluoroalkanes such as perfluorooctylbromide.

Compositions of the invention that are in the form of a clear liquid solution are also substantially free of a dissolved pharmacological active ingredient other than a semi-fluorinated alkane. As used herein, the term "pharmacological active principle" refers to any type of pharmaceutically active compound or drug, that is, one that produces a pharmacological effect and that, consequently, may be useful in prevention, diagnosis. , stabilization, treatment, or in general terms, the management of a condition or disease.

The compounds of the invention, as well as the compositions that comprise it, whether free or pharmacologically active principles, nevertheless have beneficial therapeutic effects at the site of administration.

In a further preferred embodiment, the compositions of the invention consist essentially of a compound characterized by the general formula CF3- (CF2) n-CH (CH3) - (CH2) m-CH3 where n is 5 and m is 5, and optionally, one or more lipophilic liquid constituents. In a particular embodiment, the composition consists essentially of the compound CF3- (CF2) 5-CH (CH3) - (CH2) 5-CH3, and optionally one or more lipophilic liquid constituents. As used herein, "Consist essentially of" is the so-called closed language, which means that only the mentioned constituents are present. Rather, the terms "comprise", "comprise" and "comprising" are used herein and are so-called open language, which means that additional constituents may also be present.

The optional lipophilic liquid constituents are preferably substantially water-insoluble and / or water-non-missible excipients, for example oily excipients such as lipids, triglyceride oils and any other oils that are physiologically tolerated by the eye, or other semi-fluorinated alkanes such as in the class belonging to the general formula CF3 (CF2) n (CH2) mCH3, where n and m are integers selected independently from the range 3 to 8, for example, for example, CF3 (CF2) 3 (CH2) 4CH3 or CF3 (CF2) 5 (CH2) 7CH3. Such lipophilic liquid constituents may be present in the composition in amounts up to about 25% by weight, or up to about 50% by weight, or 75% by weight, or 90% by weight, 95% by weight, or 97% by weight. of the composition, based on the total weight of the composition.

In a preferred embodiment, the composition according to the present invention comprises or essentially consists of CF3- (CF2) 5-CH (CH3) - (CH2) 5-CH3 and CF3- (CF2) 5- (CH2) 7-CH3 .

The compounds of the invention, as well as the compositions comprising the same, even if they are free from other pharmacologically active principles, nevertheless have beneficial therapeutic effects at the point of administration.

The compositions as defined above are preferably formulated so that they have a dynamic viscosity of no more than 10 mPas, and preferably no more than 4 mPas, as determined under conditions of pressure and ambient temperature (25 ° C, 1 atm.). Preferably, the compositions have a dynamic viscosity of between 1 and 4 mPa s. The viscosity of the compositions can be determined using any conventional viscometer device known in the art, such as a glass tube or a capillary viscometer.

The compounds characterized by the general formula CF3- (CF2) n- (CH2) m-CH3 in which n is 5 and m is 5 and the compositions thereof described herein can be used in medical applications, in particular for use in ophthalmology, and in particular in topical administration to the eye, such as to the lacrimal sac, the interior of the lower eyelid, to an ocular surface or any ophthalmic tissue or anatomy associated with the eye that may be available for topical administration.

In particular, the compounds of the invention are beneficial for use in treating diseases and conditions that could benefit from stabilization of the tear film and lipid layer of the tear film and lubrication of the ocular surface. Thus, the compositions of the present invention are especially adapted to the treatment of dry eye disease (keratoconjunctivitis sicca) and / or Meibomian Gland Dysfunction (MGD) and any symptoms thereof or associated therewith.

Dry eye disease, also known as keratoconjunctivitis sicca, can be distinguished into two categories, namely water-deficient dry eye disease and evaporative dry eye disease. These conditions are not necessarily mutually exclusive. Typically, water-deficient dry eye disease is seen in patients suffering from Sjogren's syndrome, or those suffering from tear gland insufficiency, tear duct obstruction, or reflex hyposecretion. Evaporative dry eye disease on the other hand has various causes and is associated with abnormal / increased evaporative loss of the tear film, for example as a result of disorders in the Meibomian gland, eyelid opening disorders, blindness disorders or ocular surface disorders.

Symptoms of dry eye disease include dryness, a feeling of roughness, sand, or a foreign body inside the eye; pain, swelling, stinging, or burning; itching, increased need to blink, eye fatigue, photophobia, blurred vision, redness and inflammation of the eye tissue, excess mucosal discharge and crusting / clotting, contact lens intolerance, and excess reflex tearing.

Meibomian Gland Dysfunction (MGD) refers to a condition in which the meibomian glands do not secrete enough oil or when the oil secretion is poor or of abnormal quality. Often times, the oil gland openings can become clogged or clogged so that less oil is secreted into the glands. The oil that is secreted into the glands can be granular (crusty) or abnormal, and can cause irritation to the eye. In the early stages, the patient is often asymptomatic, but if left untreated, MGD can cause or exacerbate symptoms of dry eye and eyelid inflammation. The oil glands become blocked due to thick secretions. Eventually, chronically clogged glands lose their ability to secrete oil, which can result in permanent tear film changes and dry eyes.

Symptoms of Meibomian Gland Dysfunction include dryness, burning, itching, feeling greasy / stiff, light sensitivity with tearing, eye redness, foreign body sensation, chalazion / stye, or intermittent blurred vision.

In a preferred embodiment of the invention, the compounds and compositions thereof, as described above, are used for the topical ophthalmic treatment of evaporative dry eye disease or Meibomian Gland Dysfunction, and relief of any one of the symptoms associated with them.

In one embodiment of the invention, the ophthalmic composition comprising a semi-fluorinated compound characterized by the general formula CF ³ - (CF ² ) ⁿ -CH (CH ³ ) - (CH ² ) ^m -CH ³ in which n is 5 and m is 5 (i.e. formula CF ³ - (CF ² ) ⁵ -CH (CH ³ ) - (CH ² ) ⁵ -CH ³ is used for the treatment of dry eye disease (keraconjunctivitis sicca) or a symptom associated with In another embodiment, such a composition can be used for the treatment of Meibomian Gland Dysfunction or a symptom associated therewith.

In further embodiments, the treatment of these conditions is preferably carried out by a method of feeding a patient in need thereof, an effective amount of a composition consisting essentially of said semi-fluorinated alkane, and optionally one or more lipophilic liquid constituents that they are preferably excipients not soluble in water and / or not miscible in water, for example oily excipients such as lipids, triglyceride oils and any other oils that are physiologically tolerated by the eye, or other semi-fluorinated alkanes such as in the class belonging to the formula general CF ³ (CF ² ) ⁿ (CH ² ) ^m CH ³ , where n and m are whole numbers independently selected from the range 3 to 8, for example, CF ³ (CF ² ) ³ (CH ² ) ⁴ CH ³ or CF ³ (CF ² ) ⁵ (CH ² ) ⁷ CH ³ .

In a further preferred embodiment of the invention, the compounds and compositions thereof described above are used for the topical ophthalmic treatment of damage to the cornea. Thus, such compounds and compositions actively contribute to the healing process of corneal damage, such as corneal erosions.

The advantages of the compounds described above in the context of their use according to the present invention are thought to be related to their properties, which are particularly adapted for ophthalmic applications. The close proximity of the refractive indices of the compounds of the invention to that of water, means that they could have little or no impact on the patient's vision after administration, unlike ophthalmic compositions based exclusively on vehicles that can confer blurred vision after administration. Generally, the low viscosity and low surface tension and in particular the high wettability and dispersion capacity of these compounds also ensure that they adapt and settle quickly after administration to the ocular surface.

As may be more apparent from the following examples, the compounds and compositions thereof were found to be biocompatible and exhibit no obvious cytotoxic effects. Furthermore, it has been established that said compounds and their compositions are not only well tolerated by the eye, and also provide a beneficial effect in terms of lubrication of the eye and stabilization of the tear film, in the form of releasing the patient's symptoms that has mild to moderate symptoms associated with dry eye disease and / or Meibomian Gland Dysfunction. Patients with dry eye disease and / or meibomian gland dysfunction often express a thicker and more opaque meibomian, which can lead to an abnormal lipid layer in the tear film. Without wishing to be bound by any theory, it is believed that the physicochemical attributes of the compounds of the invention may play a role in stabilizing the lipid layer of the tear film, such as by solubilization of certain lipid components or the improvement of the fluidity of the lipid layer.

In a further aspect, the present invention provides a method of treating dry eye disease and any symptoms and conditions associated therewith, comprising administering the compositions of the present invention topically to the lacrimal sac, the interior of the lower eyelid. , to the ocular surface or to ophthalmic tissue. Preferably, such compositions can be administered to the eye or ocular tissue up to four times a day.

Furthermore, the invention provides a kit comprising any one of the compositions described above, and a container to house said composition. Said container preferably comprises a dispensing means adapted for topical administration of the composition to the ocular sac, lower lid to an eye or ophthalmic tissue, such as an ocular dropper.

In a further preferred embodiment, the dispensing means comprises a dropper of such dimensions that it dispenses drops having a volume of approximately 8 to 15 µl, preferably having a volume of approximately 8-12 µl, more preferably having a volume of approximately 10 µl. pl. With a small droplet volume, accurate dosing to the eye can be achieved and an excessive amount of discharge of the substantial fraction of the composition from the eye after administration can be avoided.

Examples

Preparation of CF ³ - (CF ² ) ⁵ -CH (CH ³ ) - (CH ² ) ⁵ -CH ³ (2-perfluorohexyl-octane, C ¹⁴ F ¹³ H ¹⁷ )

The compound CF ³ - (CF ² ) ⁵ -CH (CH ³ ) - (CH ² ) ⁵ -CH ³ can be prepared as follows: addition of perfluorohexyl iodide radicals with 1-octene in the presence of an initiator of radicals (here perfluorohexyl iodide is mixed with 1-octene and a radical initiator such as AlBN and the solution obtained is kept at 80 ° C for 30 minutes and cooled), followed by reduction of the resulting iodine adduct with hydride (i.e., LiAlH ⁴ ) or by means of hydrogenation (i.e., catalytic hydrogenation in the presence of a catalyst such as Pd / C) to form 2-perfluorohexyl-octane, followed by purification by means of fractional distillation. Other compounds of formula CF ³ - (CF ² ) ⁿ -CH (CH ³ ) - (CH ² ) ^m -CH ³ as defined above can be prepared analogously by this general method.

CF ³ - (CF ² ) ⁵ -CH (CH ³ ) - (CH ² ) ⁵ -CH ^{3: 1} H NMR (CDCl ³ , 400 MHz); 2.17-2.33 (m, 1H, CH), 1.67-1.77 (m, 2H, CH ² ), 1.25 1.40 (m, 8H, CH ² ), 1.15 ( d, 3H, CH ³ ), 0.90 (t, 3H, CH ³ ).

Preparation of CF3- (CF2) 3-CH (CH3mCH2H-CH3 (2-Perfluorobutyl-pentane. C ⁹ F ⁹ H ¹¹ )

(Reference example)

The compound CF ³ - (CF ² ) ³ -CH (CH ³ ) - (CH ² ) ² -CH ³ can be prepared according to the general method described above with perfluorobutyl iodide and 1-pentene as starting materials.

CF ³ - (CF ² ) ³ -CH (CH ³ ) - (CH ² ) ² -CH ³ : ¹ H-NMR (CDCl3, 400 MHz): 2.21-2.32 (m, 1H, CH), 1.68-1.74 ( m, 2H, CH ² ), 1.45 1.55 (m, 2H, CH ² ), 1.12 (d, 3H, CH ³ ), 0.92 (t, 3H, CH ³ ).

In vitro cytotoxicity assay

The cytotoxicity of a composition comprising 1.3% by weight of CF ³ - (CF ² ) ⁵ -CH (CH ³ ) - (CH ² ) ⁵ -CH ³ and 95.8% by weight of CF3 was evaluated (CF2) s (CH2) 7CH3 by means of a cell proliferation inhibition assay that predicts cytotoxic or necrotic effects with good correlation with animal experiments and high sensitivity.

The composition was extracted thanks to a cell culture medium (DMEM supplemented with 10% FBS) under shaking for ~ 24 hours. Subsequently, the resulting extract was incubated with mouse cell line L929 cells for 68-72 hours, before analyzing the protein content using a BCA (bicinchoninic acid) assay as a measure of cytotoxicity. No inhibition of cell proliferation or cell lysis was observed.

An analogous in vitro cytotoxicity test was carried out for a composition comprising about 23.7% by weight of CF ³ - (CF ² ) ⁵ -CH (CH ³ ) - (CH ² ) ⁵ -CH ³ and about 75.6% of F6H8.

Tear film analysis studies

A composition comprising 98.3% CF ³ (CF ² ) ⁵ (CH ² ) ⁷ CH ³ and 1.2% by weight CF ³ - (CF ² ) ⁵ -CH (CH ³ ) was tested. ) - (CH ² ) ⁵ -CH ³ in an observational study in patients with mild to moderate evaporative dry eye disease. The clear, colorless liquid composition was provided in a 5 ml bottle fitted with a dropper sized to provide approximately 10 µl drops into the eye sac. Patients who wore contact lenses were excluded from the study. After obtaining informed consent, patients were advised to apply 3-4 drops daily in both eyes, which resulted in a daily dose of 30-40 pl. The patients returned after 5-7 weeks for a follow-up visit. Clinical data from 29 patients were collected at the initial visit and the follow-up visit at 5-7 weeks.

a) Tear film analysis

Film flow and tear film stability improved after the study period, as can be seen in the increase in Schirmer I and TFBUT. Retrospective statistical analysis corroborates this observation, since the difference in TFBUt at the initial visit and the follow-up visit is highly significant (paired bilateral t test: p = 0.0026 (right eyes) and p = 0.0006 (eyes left)). No changes were detected in the osmolarity of the tear.

The subjective questionnaire on ocular dryness (Ocular Surface Disease Index, OSDI) revealed that the severity of the subjective symptoms of the patient decreased after the use of the composition that comprised 98.3% by weight of CF3 (CF2) 5 (CH2) 7CH3 and 1.2% by weight of CF3- (CF2) 5-CH (CH3) - (CH2) 5-CH3 for a period of 5-7 weeks, as can be seen in the lower scores in the follow-up and analysis Retrospective statistical (two-tailed t-test with pairing: p <0.0001).

b) Corneal staining (Oxford Gradation Scheme)

Fluorescein staining of the cornea is an indicator of corneal damage (loss of cell-cell junctions). The data indicate a reduction in corneal damage after 5-7 weeks of treatment, as can be seen in the change in the number of patients diagnosed with Grade 1 or 2 at the initial visit versus Grade 0 at the follow-up visit. This difference with the initial level of damage was statistically significant, as shown by the Wilcoxon test of paired samples: p = 0.0013 (right eyes) and p = 0.0041 (left eyes).

c) Assessment of symptoms by a physician

The physician asked the patients if they currently had typical symptoms of dry eyes at both the initial visit and the follow-up visit. As can be seen in the table below, a smaller number of symptoms associated with DED were noted after 5-7 weeks of treatment.

d) Meibomian secretion analysis

In the healthy eye, the meibomian is secreted by the meibomian glands as a clear liquid. The More opaque or thick meibomian is an indicator of meibomian gland dysfunction. The patient's meibomium was descriptively examined, both at the initial visit and at follow-up. According to the data obtained, the quality of the meibomium improved in a number of cases. In seven cases, the treatment induced an expressible reduction in meibomium (change from transparent meibomium to none)

e) Security parameters

No changes were observed in either visual acuity or intraocular pressure, indicating that the use of the composition comprising 98.3% of CF ³ (CF ² ) ⁵ (CH ² ) ⁷ CH ³ and 1.2 % by weight of CF3- (CF2) 5-CH (CH3) - (CH2) 5-CH3 for 5-7 weeks is safe and does not interfere with these ophthalmic parameters.

Differential Scanning Calorimetry

Differential scanning calorimetry (DSC 1, Mettler Toledo, Greinfensee, Switzerland) is used to characterize the structure and phase behavior of mixtures of CF3 (CF2) 5CH (CH3) (CH2) 5CH3 and CF3 (CF2) 5 (CH2 ) 7CH3. DSC was used to obtain the data of the transitions by increasing temperature sweeps with a heating rate of 1 ° C / minute. Standard sealed aluminum crucibles (40 pl, Mettler Toledo) were used.

Merger Transition

% wt CF3- (CF2) 5-CH (CH3) - (CH2) 5-CH3

-24,09 -21,56 -15,38 -14,17 AH (J / g) Beginning (° C) Maximum (° C) End (° C) 0 -36.57 -6.33 -4.53 -2.14 5.91 -33.36 -10.32 - 7.99 -7.24 12.0 -29.42 -13.74 -10.44 -9.58 23.7

-24.09 -21.56 -15.38 -14.17

Low temperature transition

% wt CF3- (CF2) 5-CH (CH3) - (CH2) 5-CH3

-0,19 -60,75 -54,39 -52 AH (J / g) Beginning (° C) Maximum (° C) End (° C) 0 -0.69 -45.47 -40.37 -38.32 5.91 -0.56 -50.61 - 45.77 -42.93 12.0 -0.44 -55.18 -48.58 -45.53 23.7

-0.19 -60.75 -54.39 -52

The presence of CF3 (CF2) 5-CH (CH3) - (CH2) 5-CH3 in a mixture of CF3 (CF2) 5- (CH2) 7-CH3 (F6H8) results in a significant reduction in melting temperature . It also decreases the enthalpy of fusion, suggesting that this semi-fluorinated alkane does not crystallize. Said differences have a beneficial effect with respect to the application of the present compound to the eye in the form of a tear film substitute or lubricant; for example in terms of its ability to mix and modulate the lipid layer of the tear film. Said effects can also be advantageously adjusted by varying the amounts of the present compound that are added to the ophthalmic compositions.

DSC measurements of series of mixtures of 23.74% by weight of CF ³ (CF ² ) ⁵ -CH (CH ³ ) - (CH ² ) ⁵ -CH ³ and CF ³ (CF ² ) were also carried out. ⁵ - (CH ² ) ⁷ -CH ³ with tetradecane (C14). Transition data were obtained with increasing temperature sweeps (heating rates of 0.2, 0.5, and 1 ° C / minute). Extrapolation at a heating rate of 0 ° C / minute was used to determine the end temperatures, although the averages of these three measurements were used to determine the start temperature. A decrease in the enthalpy of fusion was observed, compared to the mixtures of tetradecane with pure CF ³ (CF ² ) ⁵ - (CH ² ) ⁷ -CH ³ , which suggests that part of the tetradecane dissolves in the liquid fraction of CF ³ (CF ² ) ⁵ -CH (CH ³ ) - (CH ² ) ⁵ -CH ³ and that this compound has a more intense dissolving capacity compared to CF ³ (CF ² ) ⁵ (CH ² ) ⁷ CH ^{3 .}

Refractive index and evaporation time

The evaporation time of mixtures of CF ³ (CF ² ) ⁵ (CH ² ) ⁷ CH ³ (F4H5) and CF ³ (CF ² ) ⁵ -CH (CH ³ ) - (CH ² ) ⁵ -CH ³ ( reference example). A 10 gl drop of each mixture was placed on a glass surface at room temperature. The time to evaporation was recorded by video-control.

It was observed that an increase in the amount of the compound CF ³ - (CF ² ) ³ -CH (CH ³ ) - (CH ² ) ² -CH ³ appears to increase the evaporation time of the mixture (see Fig. 1).

The evaporation time of mixtures of semifluorinated alkane CF ³ (CF ² ) ⁵ (CH ² ) 7CH ³ (F6H8) and CF ³ (CF ² ) ⁵ -CH (CH ³ ) - (CH ² ) ⁵ -CH was analogously evaluated ³ .

On the contrary, it was unexpectedly observed that an increasing percentage of the semifluorinated alkane CF ³ (CF ² ) ⁵ -CH (CH ³ ) - (CH ² ) ⁵ -CH ³ significantly decreases the evaporation time of the mixtures (see Figure 1) .

Thus, depending on the compound characterized by the general formula CF ³ - (CF ² ) ⁿ -CH (CH ³ ) - (CH ² ) ^m -CH ³ in which n is an integer selected from 3 to 5 and m is a A selected integer from 1 to 5 and the amount present in the mixture, it may be possible to tailor and fine tune the composition to the requirements of the desired ophthalmic use, such as in terms of prolonging or reducing the residence time of the composition on the surface of the eye.

The refractive index of the mixtures was also determined. For topically applied ophthalmic compositions, the refractive index should preferably be similar to, or adapted to, that of the eye and the lens, for example, as close as possible to that of the physiological tear fluid. If the refractive index of the composition is not similar, when applied to the surface of the eye, the patient may experience blurred sensation or decreased vision. It is appreciated that the amount of compound CF ³ (CF ² ) ⁵ -CH (CH ³ ) - (CH ² ) ⁵ -CH ³ has an effect on the refractive index. Fig. 2 shows an increase in the refractive index value with increasing content of 2-perfluorohexyloctane in a mixture with 1-perfluorohexyloctane. Fig. 3 also shows an increase in the refractive index value with an increase in the content of 2-perfluorobutylpentane in a mixture with 1-perfluorobutylpentane.

By varying the amount of these compounds, such as characterized by the general formula CF ³ - (CF ² ) ⁿ -CH (CH3) - (CH2) ^m -CH3 in which n is an integer selected from 3 to 5 and m is a A selected integer from 1 to 5 in the mixture, it may also be feasible to adapt the composition to the requirements of the desired ophthalmic use, for example, by adaptation to a patient with refractive index and modified tear fluid composition, due to an ocular condition and / or age.

Ex vivo Eye Irritation Test (EVEIT)

A comparison was made with respect to the corneal healing process for two compositions comprising CF ³ (CF ² ) ⁵ (CH ² ) ⁷ -CH ³ , specifically compositions consisting of a mixture of semi-fluorinated alkane CF3 (CF2) 5 (CH2) 7-CH3 and CF3 (CF2) 5-CH (CH3) - (CH2) 5-CH3 (Composition A with 0.17% by weight of CF3 (CF2) 5-CH (CH3) - (CH2 ) 5-CH3 and Composition B, with 64% by weight of CF3 (CF2) 5-CH (CH3) - (CH2) 5-CH3) with hyaluronic acid (HYLO-COMOD®) as reference and 0.01% of BAC (benzalkonium chloride) as a positive control using the Ex Vivo Eye Irritation Assay (EVEIT), similar to that described in M. Frentz et al., Altern. To Lab. Anim., 2008 (36) p 25-32; and N. Scharge et al, Graefes Arch Clin Exp Ophthalmol 2012 (250), 1330-1340).

Method. Rabbit corneas were obtained and placed in an artificial anterior ocular chamber that was gently filled with minimal serum-free essential medium (MEM Eagle) containing Earle's salts and HEPES buffer for nutrition. The medium was constantly replaced by means of a micropump to mimic the physiological condition of the eye. The culture chambers were kept at 32 ° C in normal air, without supplementary CO ² and> 95% relative humidity. Five corneas per test substance (n = 5) were used except for the positive control for which two corneas (n = 2) were tested.

After 12 hours of stabilization in the culture chamber, the corneas were evaluated by means of microscopy and the corneas with intact epithelium and without opacities were selected. Four small abrasions (2.3 4.3 mm2) were applied to the surface of the selected corneas with a corneal piercer. All defects were evaluated by staining with sodium fluorescein (0.17% aqueous solution) and microscopy.

The test substances were administered one hour after the induction of corneal erosion and applied six times a day on the apex of the corneas (30-50 gl every four hours). A soft-tipped cannula, with continuous suction, was placed over the lowermost part of the corneo-scleral region within the culture chamber to remove excess fluid. The experiments were concluded 3 days after the application. Biomicroscopic images of the corneas were taken daily to document the corneal healing process using an integrated phase contrast microscope camera (KY-F1030U, JVC, (Bad Vilbel, DE) mounted on a Z16 APO Microscope (Wetzlar, DE). )). All defects were evaluated by staining with sodium fluorescein (0.17% aqueous solution), so that yellow and green fluorescence indicated the areas of epithelial defects. Erosion sizes were determined using a microscope software tool (DISKUS). At the end of 3 days, the experiment was terminated and all corneas were fixed in 3.7% formaldehyde and stained with a hematoxylin-eosin stain for microscopic evaluation. To evaluate the metabolic activity of the cornea, glucose and lactate concentrations were quantified photometrically in the outlet medium from the artificial anterior chambers.

Results. It was observed that both semi-fluorinated alkane mixtures (Composition A and B as referenced above) had a positive effect with respect to the corneal healing process after the induction of erosion in the cornea, compared to the reference composition. conventional hyaluronic acid (HYLO-COMOD®).

Corneal erosion size measurements / mean mm2 (SD)

Day 3 Histological observations

There were no significant differences in terms of positive corneal healing between Composition B containing 64% by weight, based on the total weight of the composition, of semi-fluorinated alkane CF3 (CF2) 5-CH (CH3) - (CH2 ) 5-CH3 and composition A. With both compositions, as with the reference composition, it was found that the epithelial erosions induced by the mechanical route were significantly reduced and were essentially absent after 2 days of treatment. Figure 3 shows the corneal erosion size measurements of the tested, reference, and positive control compositions for days 0-3 of the EVEIT experiment.

As can be seen in the table above, the microscopic histological examination of the corneas cross-sections after the conclusion of the experiment on day 3, revealed no significant or different remaining effects in the corneas treated with compositions A, B and HYLO-COMOD® reference.

Furthermore, no corneal toxicity was noted, based on metabolic activity as indicated by glucose / lactate measurements for these compositions.

In significant contrast, the positive control that comprised 0.01% of the BAC preservative, a progressive increase in induced epithelial lesions was observed during the course of the three days of the experiment.

Claims (11)

1. An ophthalmic composition comprising the compound characterized by the general formula CF ³ (CF ² ) ⁵ (CH ² ) ⁷ CH ³ and CF ³ (CF ² ) ⁵ -CH (CH ³ ) - (CH ² ) ⁵ -CH ³ where n is 5 and m is 5. The composition according to claim 1, which is in liquid form and which comprises at least 1% by weight of the compound based on the total weight of the composition. 3. The composition according to any one of the claims, which is formulated as a transparent liquid solution. 4. The composition according to any one of the preceding claims, which is free of: (a) a polymer, (b) a perfluorinated compound, and / or (c) a dissolved pharmacologically active ingredient that is not a semi-fluorinated alkane. The composition of claim 1, consisting essentially of the compound and optionally one or more lipophilic liquid constituents. 6. The composition according to any of the preceding claims for use as a medicine. The composition for use according to claim 6, wherein the composition is administered topically into the lacrimal sac, into the lower eyelid, to an ocular surface, or to ophthalmic tissue. The composition for use according to claim 6 or 7 in the treatment of dry eye disease (keratoconjunctivitis sicca) and / or Meibomian gland dysfunction or a symptom or condition associated therewith, wherein the symptoms or conditions associated with keratoconjunctivitis sicca comprise sensations of dryness, a sensation of roughness, sand or a foreign body inside the eye; pain, swelling, stinging, or burning; itching, increased need to blink, eye fatigue, photophobia, blurred vision, redness and inflammation of eye tissue, excess mucosal discharge and crusting / clotting, contact lens intolerance and excess reflex tearing; where the symptoms or conditions associated with meibomian gland dysfunction include dryness, burning, itching, greasy / stiff sensation, light sensitivity with tearing, eye redness, foreign body sensation, chalazion / stye, or blurred vision intermittent. The composition for use according to claims 6 to 8 in the treatment of damage to the cornea. 10. A kit comprising an ophthalmic composition according to any of claims 1 to 5 and a container for housing the composition, wherein said container comprises a dispensing means adapted for topical administration of the composition to the lacrimal sac, inside the eyelid , ocular surface or ophthalmic tissue. The kit of claim 10, wherein the dispensing means comprises a dropper with dimensions that delivers drops having a volume of 8 to 15 µl.